Core B, the Antibody / Ig Fusion Core, provides an important means by which the PPG will achieve its goals of understanding the immune response in tolerance, autoimmunity and infection. Core B will coordinate the use of mAb and Ig fusion proteins to enable the study of the roles of the PD-1 and other coinhibitory pathways in regulating immune responses during acute and chronic infection, chronic graft versus host disease (cGVHD), and autoimmunity. To achieve these goals Core B has the following aims:
Aim 1 : To maintain and produce existing and newly generated mAbs and Ig fusion proteins for PPG investigators. An extensive set of mAbs and fusion proteins against coinhibitory molecules has been generated in the first cycle of this PPG and these will continue to be produced as well as characterized for additional activities.
Aim 2 : To generate novel monoclonal antibodies and Ig fusion proteins to study the function and expression of coinhibitory receptors and ligands. RGMb and PROCR are newly identified co-inhibitory molecules that impact T cell exhaustion and the PD-1 pathway. Core B will generate novel antibodies that will facilitate analysis of the function and expression of coinhibitory molecules particularly PD-1/PD-L, RGMb, and PROCR pathway members as well as other coinhibitory pathways. These include novel mouse anti-mouse antibodies made in knockout mice that see novel epitopes including anti-PD-1, PD-L1, PD-L2 for long-term treatment of mice without anti-antibody responses. These novel mouse anti-mouse mAbs will also be made as recombinant mAbs with mutated Fc to eliminate effects due to cell depletion or FcR signaling. This best models PD-1 mAbs used in clinical trials. Core B will generate novel multimeric Ig fusion proteins of these coinhibitory pathway proteins in order to either block or transduce signals via cross-linking receptors. The production of these critical reagents by a core not only will be time and cost efficient, but also provide standardized reagents that will facilitate comparison of data by investigators in this PPG. Core B will work closely with all PPG investigators, providing mAbs and Ig fusion proteins and identifying new needs. These reagents will allow PPG investigators to develop a comprehensive understanding of the roles of positive and negative second signals in modulating T cell activation, tolerance and exhaustion. The production of these critical reagents by a core not only will be time and cost efficient, but also provide standardized reagents that will facilitate comparison of data by investigators in this PPG.
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|Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao et al. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 74:3441-53|
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